3-halogeno-bis-nor-allo-cholanic acid compounds and a process for producing them



Patented Oct. 21, 1941 UNITED STATES PATENT OFFICE 3-HALOGENO-BIS NORALLO CHOLANIC ACID COIVHOUNDS AND A PROCESS FOR PRODUCING THEM RussellEarl Marker, State College, Pa., assignor to Parke, Davis & Company,Detroit, Mich., a

corporation of Michigan No Drawing.

1937, Serial No. 157,775.

Original application August 6,

Divided and this allplication September 26, 1938, Serial No. 231,817

7 Claims.

H: 4, CH; H-CHI-COOCHI l o iMBBr ii Methyl ester ofS-ehloro-allo-nor-cholanic acid (M. P. 178 C.)

CH: Ca s CH: H-CHr-G CeH| AA l Oxidize I (o. g. CFO!) Cl 2\/ H3-ehloro-allo-bis-nor-cholanyl-dipbenyl carbinol (M. P. 183 0.) 40

EH1 C B 3-0 0 OH B-chloro-bis-nor-allo-cholanic acid (231 C.)

Esteriiy (e. g. using CHLOE) CH: 7 H-COOCHI Methyl ester oi3-chloro-bis-nor-allo-eholeuic acid (M. P. 151 C.)

The methyl ester 01. 3-chloro-nor-allo-oholanic acid has a melting pointof 178 C. It may be obtained in accordance with any known process. Inthe parent application, above referred to, the steps or obtaining thesame from 3-chloro-allocholanic acid are given and these are also setforth in the following examples. Examples are also subsequently given ofthe steps in the conversion of the methyl ester of3-ohloro-nor-allocholanic acid into the esters of3-chloro-bis-norallo-cholanic acid.

It is to be understood that while the ohloro derivatives are describedin detail, the other halogeno derivatives are included within the scopeof the invention as the steps in obtaining the other halogeno compoundsare similar to those specifically set forth.

Preparation of 3-chZoro-allo-cholanic acidAlpha-Ii-chloro-allo-cholancic acid This compound is prepared from theringsaturated sterol halide, alpha-cholestyl chloride, by chromic oxideoxidation as described by Marker, Whitmor and Kamm, J. A. C; 8., volume57, pages 2358-60, December, 1935. It crystallizes from acetone and hasa melting point 180 C.

Preparation of the methyl ester of 3-chloro-allocholanic acid 1 cc. ofconcentrated sulfuric acid is added to a solution of 100 grams of3-chloro-allocholanic acid, 111. pt. 180 C., in 3 liters of methylPreparation of 3-chZoro-allo-nor-cholanyldiphem/Zcarbinol 1 A solutionof 27 grams of methyl-3-chloroallo-cholanate in 800 cc. of ether isadded over a period of one hour to a stirred and gently refluxingsolution of 0.27 mole of phenyl magnesium bromide in 600' cc. of ether.The solution is stirred and refluxed for 4 hours, after which the etheris distilled oil? until the temperature of the remaining solutionreaches 40 C. Most of the solids dissolve at this point to form a clearsolution. The solution is maintained at 40 for one hour, decomposed with1 liter of dilute sulfuric acid and extracted with ether. The ethersolution is washed with water and concentrated to 200 cc. 200 cc. ofmethyl alcohol is added to the concentrated ether solution and theresulting solution is further concentrated to 250 cc. When this solutionis cooled and shaken, the carbinol crystallizes out as a white solid.This is recrystallized from methyl alcohol and then has a melting pointof 171 C.

1 Anal. Calcd. for C3sH49OC1: C, 81.1; H, 9.2. Found: C, 81.1; H, 9.3.

Preparation of 3-chloro-nor-allo-cholanic acid 3 A solution of 14.3grams of chromic oxide in 140 cc. of 90% acetic acid is added over aperiod of minutes to a solution of 19 grams of31-chloro-nor-allo-cholanyl diphenylcarbinol in 3'75 cc. of glacialacetic acid at 90. The solution is stirred an additional 3 hours at 90,cooled to room temperature and 1800 cc. of 10% hydrochloric acid isadded slowly with shaking. The mixture is allowed to stand overnight andfiltered. The solid which is filtered off is stirred with 100 cc. ofboiling methanol, cooled and filtered. The solid is then washed withcold methanol, leaving a crystalline product free of benzophenone. Thisis recrystallized from methanol and shows a melting point of 248 C. Theyield is 10.5 grams of crystals.

Analysis. Calculated for CzaHazOzCl: C, 72.5; H, 9.8. Found: C, 72.8; H,9.6

Preparation of the methyl ester of 3-chloronor-allo-cholanic acid Anal.Calcd. for 0241-1390201: C 73.0; H, 10.0.

Found: C, 73.3; H, 10.2.

Preparation of 3-chloro-allo-bis-nor-cholanyldiphenylcarbinol A solutionof 27- grams of methyl-3-chloroallo-nor-cholanate in 800 cc. of ether isadded over a period of one hour to a stirred and gently refluxingsolution of 0.27 mole of phenyl magnesium bromide in 600 cc. of ether.The solution is ,,s tirred and refluxed for 4 hours, after which theether is distilled ofi until the temperature of the remaining solutionreaches 40 C. Most of the solids dissolve at this point to form a clearsolution. The solution is maintained at 40 for one hour, decomposed with1 liter of dilute sulfuric acid and extracted with ether.

Preparation of 3chloro-bis-n0r-allocholanic acid A solution of 14.3grams of chromic oxide in 140 cc. of acetic acid is added over a periodof 25 minutes to a solution of 19 grams of3-chloro-allo-bis-nor-cholanyl diphenylcarbinol in 375 cc. of glacialacetic acid at 90. The solution is stirred an additional 3 hours at 90,cooled to room temperature and 1800 cc. of 10% hydrochloric acid isadded slowly with shaking. The mixture is allowed to stand overnight andfiltered. The solid which is filtered off is stirred with cc. of boilingmethanol, cooled and filtered. The solid is then washed with coldmethanol, leaving a crystalline product free ofv benzophenone. This isrecrystallized from methanol and shows a melting point of 231 C.

Preparation of the methyl ester of 3-chlorobis-ncr-allo-cholanic acid 15cc. of concentrated sulfuric acid is added to a solution of 100 grams of3-chloro-bis-norallo-cholanic acid, 111. pt. 231 C., in 3 liters ofmethyl alcohol. The solution is refluxed for 2 hours with distillationof the alcohol in the meantime to a volume of about 500 cc. The solutionis cooled to obtain a crystalline product which is then recrystallizedfrom methyl alcohol and shows a melting point of 151 C.

Other esters of 3-chZoro-bis-n0r allo-cholanic acid In the precedingexample, the methyl ester of 3-chloro-bis-nor-allo-cholanic acid wasdescribed. Other esters may be obtained by the same process by replacingthe methyl alcohol with other alcohols such as ethyl, propyl and butylalcohols. The corresponding ethyl, propyl and butyl esters of3-chloro-bis-nor-allocholanic acid are thereby obtained.

As previously stated, the compounds of the invention are not limited tothe chloro derivatives but the invention includes other halogeno tain anester oi 3-halogeno-bis-nor-a110-cholanic acid.

2. A 3-ch1oro-bis-nor-allo-cholanic acid.

3. A 3-halogeno-bis-nor-allo-cholanic acid.

4. A compound of the group consisting of a 53-ha1ogeno-bis-nor-al1o-cholanic acid and its esters.

5. 3-ch1oro-bis-nor-a1lo-cho1anic acid having a melting point of 231 C.

6. The methyl ester 01' 3-ch1oro-bis-nor-a11o- 10 cholanic acid having amelting point of 151 C.

7. The process of preparing esters oi 3-chlorobis-nor-allo-cholanic acidwhich comprises reaction of an ester of 3-chloro-allo-nor-choianic acidwith phenyl magnesium bromide to obtain3-ch1oro-al1o-bis-nor-cholanyl-diphenylcarbinol, oxidizing the lattercompound to obtain 3-ch1orobis-nor-allo-cholanic acid, and esteriiyingthe last named compound to obtain an ester of3-chloro-bis-nor-allo-cholanic acid.

RUSSELL EARL MARKER.

